The physiology and behavior of virtually all eukaryotes, including humans, exhibits a pervasive daily rhythmicity. Many critical daily rhythms are endogenous, driven by an internal master pacemaker or biological clock, with a freerunning period of about a day (i.e. circadian). The suprachiasmatic nuclei (SCN) of the hypothalamus are the apparent site of the biological clock in mammals. The functional integrity of the SCN and the overt circadian rhythms it drives decline with age. In the aged human, this has a negative impact on health through fragmentation of sleep and endocrine rhythms. In rodents, age-related changes in circadian rhythms are correlated with losses in the SCN neuropeptide VIP and loss in SCN sensitivity to the neurotransmitter serotonin. The long-term objective of the research proposed here is to elucidate critical mechanisms of circadian pacemaker and to identify changes in these mechanisms related to the decline in circadian function during aging. We will address three questions regarding the mechanisms of SCN pacemaking and its aging: (1) What are the neurophysiological changes exhibited by SCN neurons as they oscillate? (2) What are the effects on SCN neurons and synapses of VIP and serotonIn? (3) Does compromise of neurotransmission through VIP, serotonin or GABA play a role in SCN aging? We will approach these objectives by combining patch- clamp and neural network array electrophysiology to study rodent SCN neurons in vitro. Successful completion of these experiments will reveal new and significant information regarding the fundamental mechanisms of circadian rhythmicity and the cellular basis of aging of a specific, localizable brain function. This will provide an expanded basis for understanding the underlying mechanisms of age-related disruption of biological timing where these processes are apparently deranged. The multidisciplinary approach to SCN aging afforded by coordination with our IRPG collaborators, Drs. Phyllis Wise and Marilyn Duncan, will enhance the impact of these independent research proposals.